Acute respiratory distress syndrome (ARDS) is a devastating syndrome responsible for significant morbidity and mortality. Diffuse alveolar epithelial cell death, including but not limited to apoptosis and necroptosis, is one of the hallmarks of ARDS. Currently, no detectable markers can reflect this feature of ARDS. Hyperoxia-induced lung injury is a well-established murine model that mimics human ARDS. We found that hyperoxia and its derivative, reactive oxygen species (ROS), upregulate miR-185-5p, but not miR-185-3p, in alveolar cells. This observation is particularly more significant in alveolar type II (ATII) than alveolar type I (ATI) cells. Functionally, miR-185-5p promotes expression and activation of both receptor-interacting kinase I (RIPK1) and receptor-interacting kinase III (RIPK3), leading to phosphorylation of mixed lineage kinase domain-like (MLKL) and necroptosis. MiR-185-5p regulates this process probably via suppressing FADD and caspase-8 which are both necroptosis inhibitors. Furthermore, miR-185-5p also promotes intrinsic apoptosis, reflected by enhancing caspase-3/7 and 9 activity. Importantly, extracellular vesicle (EV)-containing miR-185-5p, but not free miR-185-5p, is detectable and significantly elevated after hyperoxia-induced cell death, both in vitro and in vivo. Collectively, hyperoxia-induced miR-185-5p regulates both necroptosis and apoptosis in ATII cells. The extracellular level of EV-cargo miR-185-5p is elevated in the setting of profound epithelial cell death.

急性呼吸窘迫综合征（ARDS）是一种破坏性综合征，可导致严重的发病率和死亡率。弥漫性肺泡上皮细胞死亡，包括但不限于细胞凋亡和坏死性凋亡，是ARDS的标志之一。目前，还没有可检测的标记物能够反映ARDS的这一特征。高氧引起的肺损伤是一种完善的模拟人类 ARDS 的小鼠模型。我们发现高氧及其衍生物活性氧 (ROS) 上调肺泡细胞中的 miR-185-5p，但不上调 miR-185-3p。这一观察结果在 II 型肺泡 (ATII) 细胞中比 I 型肺泡 (ATI) 细胞中尤其显着。从功能上讲，miR-185-5p 促进受体相互作用激酶 I (RIPK1) 和受体相互作用激酶 III (RIPK3) 的表达和激活，导致混合谱系激酶结构域样 (MLK​​L) 磷酸化和坏死性凋亡。MiR-185-5p 可能通过抑制 FADD 和 caspase-8（两者都是坏死性凋亡抑制剂）来调节这一过程。此外，miR-185-5p 还促进内在细胞凋亡，这通过增强 caspase-3/7 和 9 活性来体现。重要的是，在体外和体内高氧诱导的细胞死亡后，含有细胞外囊泡（EV）的 miR-185-5p（而非游离的 miR-185-5p）是可检测到的并且显着升高。总的来说，高氧诱导的 miR-185-5p 调节 ATII 细胞的坏死性凋亡和凋亡。在上皮细胞严重死亡的情况下，EV 货物 miR-185-5p 的细胞外水平升高。